Targeting cGAS-STING pathway is a promising strategy in tumor treatment. The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of the second messenger 2'3'-cGAMP, activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING. Notably, in tumor immune microenvironment, key components of cGAS-STING pathway are transferred among neighboring cells. The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity. The membrane-based system, including extracellular vesicles transport, phagocytosis and membrane fusion transmit dsDNA, cGAMP and activated STING, enhancing the immune surveillance and inflammatory. The membrane proteins, including specific protein channel and intercellular gap junctions, transfer cGAMP and dsDNA, which are crucial to regulate immune responses. And the ligand-receptor interactions for interferons transmission amplifies the anti-tumor response. This review elaborates on the regulatory mechanisms of cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment. We further explore how these mechanisms modulate immunological processes and discuss potential interventions and immunotherapeutic strategies targeting these signaling cascades.

Tumor cells adaptively reforge their metabolism to meet the demands of energy and biosynthesis. Mitochondria, pivotal organelles in the metabolic reprogramming of tumor cells, contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells. Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation, proliferation, and differentiation of immune cells. The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics, thereby facilitating the establishment of a tumor immunosuppressive microenvironment. Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals, including cGAS-STING, TLR9, and NLRP3. Moreover, mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy. Additionally, mtROS, a crucial factor in tumorigenesis, drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment. This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles. We expect to explore the core role of mitochondria in the dynamic interplay between the tumor and the host, in order to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.

OBJECTIVES: To classify bladder cancer based on immune cell infiltration score and to construct a risk assessment model for prognosis of patients. METHODS: The transcriptome data and data of breast cancer patients were obtained from the TCGA database. The single sample gene set enrichment analysis was used to calculate the infiltration scores of 16 immune cells. The classification of breast cancer patients was realized by unsupervised clustering, and the sensitivity of patients with different types to immunotherapy and chemotherapy was analyzed. The key modules significantly related to the infiltration of key immune cells were identified by weighted correlation network analysis (WGCNA), and the key genes in the modules were extracted. A risk scoring model and a nomogram for risk assessment of prognosis for bladder cancer patients were constructed and verified. RESULTS: The immune cell infiltration scores of normal tissues and tumor tissues were calculated, and B cells, mast cells, neutrophils, T helper cells and tumor infiltrating lymphocytes were determined to be the key immune cells of bladder cancer. Breast cancer patients were clustered into two groups (Cluster 1 and Custer 2) based on immune cell infiltration scores. Compared with patients with Cluster 1, patients with Cluster 2 were more likely to benefit from immunotherapy (P<0.05), and patients with Cluster 2 were more sensitive to Enbeaten, Docetaxel, Cyclopamine, and Akadixin (P<0.05). WGCNA screened out 35 genes related to key immune cells, and 4 genes (GPR171, HOXB3, HOXB5 and HOXB6) related to the prognosis of bladder cancer were further screened by LASSO Cox regression. The areas under the ROC curve (AUC) of the bladder cancer prognosis risk scoring model based on these 4 genes to predict the 1-, 3- and 5-year survival of patients were 0.735, 0.765 and 0.799, respectively. The nomogram constructed by combining risk score and clinical parameters has high accuracy in predicting the 1-, 3-, and 5-year overall survival of bladder cancer patients. CONCLUSIONS According to the immune cell infiltration score, bladder cancer patients can be classified. And the bladder cancer prognosis risk scoring model and nomogram based on key immune cell-related genes have high accuracy in predicting the prognosis of bladder cancer patients.

OBJECTIVES: To isolate potassium ion channel Kv4.1 inhibitor from centipede venom, and to determine its primary and spatial structure. METHODS: Ion-exchange chromatography and reversed-phase high-performance liquid chromatography were performed to separate and purify peptide components of centipede venom, and their inhibiting effect on Kv4.1 channel was determined by whole-cell patch clamp recording. The molecular weight of isolated peptide Kv4.1 channel inhibitor was identified with MALDI-TOF, its primary sequence was determined by Edman degradation sequencing and two-dimensional mass spectrometry, its patial structure was established based on iterative thread assembly refinement online analysis. RESULTS: A peptide SsTx-P2 was separated from centipede venom with the molecular weight of 6122.8, and its primary sequence consists of 53 amino acid residues, showed as NH₂-ELTWDFVRTCCKLFPDKSECTKACATEFTGGDESRLKDVWPRKLRSGDSRLKD-OH. Peptide SsTx-P2 potently inhibited the current of Kv4.1 channel transiently transfected in HEK293 cell, with 1.0 μmol/L SsTx-P2 suppressing 95% current of Kv4.1 channel. Its spatial structure showed that SsTx-P2 shared a conserved helical structure. CONCLUSIONS The study has isolated a novel peptide SsTx-P2 from centipede venom, which can potently inhibit the potassium ion channel Kv4.1, and its spatial structure displays a certain degree of conservation.

cGAS-STING signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury. cGAS, a cytosolic DNA sensor, is specialized in recognizing abnormally localized cytoplasmic double-stranded DNA (dsDNA) and catalytically synthesizes the second messenger cyclic-GMP-AMP (cGAMP), which initiates a cascade of type I interferon and inflammatory responses mediated by STING. Micronucleus, a byproduct of chromosomal missegregation during anaphase, are also significant contributors to cytoplasmic dsDNA. These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture, exposing genomic dsDNA to the cytoplasm, which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities, including type I interferon and classical nuclear factor-κB (NF-κB) signaling pathways lead to senescence, apoptosis, autophagy activating anti-cancer immunity or directly killing tumor cells. However, sustained STING activation-induced endoplasmic reticulum stress, activated chronic type I interferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment, leading to immune evasion and facilitating tumor metastasis. Therefore, activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy. This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.

Tumor cells adapt their metabolism to meet the demands for energy and biosynthesis.Mitochondria,pivotal organelles in the metabolic reprogramming of tumor cells,contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells.Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation,proliferation,and differentiation of immune cells.The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics,thereby facilitating the establishment of a tumor immunosuppressive microenvironment.Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals,including cGAS-STING,TLR9,and NLRP3.Moreover,mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy.Additionally,mitochondrial reactive oxygen species,a crucial factor in tumorigenesis,drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment.This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles.We explore the core role of mitochondria in the dynamic interplay between the tumor and the host to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.

Targeting cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway is a promising strategy for tumor treatment.The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of a second messenger 2′3′-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING.Notably,in tumor immune microenvironment,key components of cGAS-STING pathway are transferred among neighboring cells.The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity.The membrane-based system,including extracellular vesicles transport,phagocytosis and membrane fusion transmit dsDNA,cGAMP and activated STING,enhances the immune surveillance and inflammatory responses.The membrane proteins,including a specific protein channel and intercellular gap junctions,transfer cGAMP and dsDNA,which are crucial to regulate immune responses.The ligand-receptor interactions for interferon transmission amplifies the anti-tumor response.This review elaborates on the regulatory mechanisms of cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment,explores how these mechanisms modulate immunological processes and discusses potential interventions and immunotherapeutic strategies targeting these signaling cascades.

Cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury.cGAS,a cytosolic DNA sensor,is specialized in recognizing abnormally localized cytoplasmic double-stranded DNA(dsDNA)and catalyzes the formation of a second messenger cyclic-GMP-AMP(cGAMP),which initiates a cascade of type Ⅰ interferon and inflammatory responses mediated by STING.Micronucleus,a byproduct of chromosomal missegregation during anaphase,is also a significant contributor to cytoplasmic dsDNA.These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture,exposing genomic dsDNA to the cytoplasm,which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities,including type Ⅰ interferon and classical nuclear factor-κB(NF-κB)signaling pathways lead to senescence,apoptosis,autophagy activating anti-cancer immunity or directly killing tumor cells.However,sustained STING activation-induced endoplasmic reticulum stress,activated chronic type Ⅰinterferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment,leading to immune evasion and facilitating tumor metastasis.Therefore,activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy.This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.

Objective:To classify bladder cancer based on immune cell infiltration score and to construct a prognosis assessment model of patients with bladder cancer.Methods:The transcriptome data and clinical data of breast cancer patients were obtained from the The Cancer Genome Atlas(TCGA)database.Single sample gene set enrichment analysis was used to calculate the infiltration scores of 16 immune cells.The classification of breast cancer patients was achieved by unsupervised clustering,and the sensitivity of patients with different types to immunotherapy and chemotherapy was analyzed.The key modules significantly related to the infiltration of key immune cells were identified by weighted correlation network analysis(WGCNA),and the key genes in the modules were identified.A risk scoring model and a nomogram for prognosis assessment of bladder cancer patients were constructed and verified.Results:B cells,mast cells,neutrophils,T helper cells and tumor infiltrating lymphocytes were determined to be the key immune cells of bladder cancer.The patients were clustered into two groups(Cluster 1′ and Custer 2)based on immune cell infiltration scores.Compared with patients with Cluster 1′,patients with Cluster 2 were more likely to benefit from immunotherapy(P<0.05),and patients with Cluster 2 were more sensitive to Enbeaten,Docetaxel,Cyclopamine,and Akadixin(P<0.05).35 genes related to key immune cells were screened out by WGCNA and 4 genes(GPR171,HOXB3,HOXB5 and HOXB6)related to the prognosis of bladder cancer were further screened by LASSO Cox regression.The areas under the ROC curve(AUC)of the bladder cancer prognosis risk scoring model based on these 4 genes to predict the 1-,3-and 5-year survival of patients were 0.735,0.765 and 0.799,respectively.The nomogram constructed by combining risk score and clinical parameters has high accuracy in predicting the 1-,3-,and 5-year overall survival of bladder cancer patients.Conclusions:According to the immune cell infiltration score,bladder cancer patients can be classified.Furthermore,bladder cancer prognosis risk scoring model and nomogram based on key immune cell-related genes have high accuracy in predicting the prognosis of bladder cancer patients.

Objective:To explore the mechanism of Anemarrhenae Rhizoma in treatment of Alzheimer's Disease(AD).Methods:The active ingredients and targets of Anemarrhenae Rhizoma for treatment of AD were screened with network pharmacology methods,the protein-protein interaction(PPI)network was constructed and the core targets were analyzed.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways enriching analysis was performed.The peripheral blood lymphocytes were extracted and lymphoblastoid cell lines(LCL)were constructed and an in vitro cell model of LCL-SKNMC was established.MTT and CCK-8 methods were used to quantify SKNMC/LCL cells,2′,7′-dichlorodihydrofluorescein diacetate(DCFH-DA)probe was used to detect reactive oxygen species(ROS),and immunofluorescence staining was used to detect the generation of Aβ1-42 in a co-cultured model.Western blotting was used to detect protein expression in the co-culture model.The lifespan of N2 nematodes was observed under oxidative stress,normal state,and heat stress;ROS generated by N2 nematodes was detected by DCFH-DA probes.The paralysis time of CL4176 N2 nematodes was evaluated by paralysis assay,and Aβ deposition in the pharynx was detected by Thioflavin S staining.Results:Through network pharmacology,15 potential active ingredients and 103 drug-disease targets were identified.PPI analysis showed that the Anemarrhenae Rhizoma might play anti-AD roles through albumin,Akt1,tumor necrosis factor,epidermal growth factor receptor(EGFR),vascular endothelial growth factor A(VEGFA),mammalian target of rapamycin(mTOR),amyloid precursor protein(APP)and other related targets.KEGG analysis showed that the pharmacological effects of Anemarrhenae Rhizoma might involve the biological processes of Alzheimer's disease,endocrine resistance,insulin resistance;and neuroactive ligand-receptor interaction,phosphatidylinositol 3-kinase(PI3K)-Akt signaling pathway,calcium signaling pathway,AGE-RAGE signaling pathway in diabetes complications,neurotrophic factor signaling pathway and others.The in vitro cell experiments showed that Anemarrhenae Rhizoma was able to reduce the production of ROS and Aβ1-42(both P<0.01),inhibit the expression of β-secretase 1(BACE1),APP and Aβ1-42 proteins(all P<0.05),up-regulate the expression of p-PI3K/PI3K,p-AKT/AKT,p-GSK3β/GSK3β in SKNMC cells(all P<0.05).The in vivo studies further confirmed that Anemarrhenae Rhizoma prolonged the lifespan of C.elegans under stress and normal conditions,reduced the accumulation of ROS and the toxicity of Aβ deposition.Conclusion:Anemarrhenae Rhizoma may reduce the production of Aβ in AD and inhibit its induced oxidative stress,which may be achieved by regulating the PI3K/Akt/GSK-3β pathway.